[ CAS No. 163733-99-1 ] {[proInfo.proName]}

Name: 163733-99-1|4-Amino-2,3-difluorophenol|95%
Brand: Ambeed
SKU: A590358
Price: 23.0 USD
Availability: InStock
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Cat. No.: {[proInfo.prAm]}

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Quality Control of [ 163733-99-1 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 163733-99-1 ]

SDS Specification

Alternatived Products of [ 163733-99-1 ]

Product Details of [ 163733-99-1 ]

CAS No. :	163733-99-1	MDL No. :	MFCD03094494
Formula :	C₆H₅F₂NO	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	LYFMJLYBTMEYDV-UHFFFAOYSA-N
M.W :	145.11	Pubchem ID :	2778766
Synonyms :

Calculated chemistry of [ 163733-99-1 ] Expand+

Physicochemical Properties

Num. heavy atoms :	10
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.0
Num. rotatable bonds :	0
Num. H-bond acceptors :	3.0
Num. H-bond donors :	2.0
Molar Refractivity :	32.79
TPSA :	46.25 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.41 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.22
Log Po/w (XLOGP3) :	1.09
Log Po/w (WLOGP) :	2.1
Log Po/w (MLOGP) :	1.68
Log Po/w (SILICOS-IT) :	1.5
Consensus Log Po/w :	1.52

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-1.87
Solubility :	1.96 mg/ml ; 0.0135 mol/l
Class :	Very soluble
Log S (Ali) :	-1.65
Solubility :	3.22 mg/ml ; 0.0222 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-2.0
Solubility :	1.45 mg/ml ; 0.01 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	2.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.18

Safety of [ 163733-99-1 ]

Signal Word:	Danger	Class:	6.1,8
Precautionary Statements:	P261-P280-P301+P310-P305+P351+P338	UN#:	2928
Hazard Statements:	H301-H315-H318-H335	Packing Group:	Ⅱ
GHS Pictogram:

Application In Synthesis of [ 163733-99-1 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Upstream synthesis route of [ 163733-99-1 ]
Downstream synthetic route of [ 163733-99-1 ]

[ 163733-99-1 ] Synthesis Path-Upstream 1~5

1
[ 868735-81-3 ]
[ 163733-99-1 ]

Yield	Reaction Conditions	Operation in experiment
92%	With hydrogen In methanol for 2 h;	A mixture of 1-benzyloxy-2,3-difluoro-4-nitrobenzene (14 g, 52.8 mmol) and Pd/C (10percent, 1.4 g) in MeOH (200 mL) was stirred under a hydrogen atmosphere (30 psi) for 2 h. The catalyst was removed by filtration and the filtrate was concentrated in vacuo to afford 4-amino-2,3difluoro-phenol (7 g, 92percent yield). ¹H NMR (400 MHz, DMSO-d₆) δ 9.05 (s, 1H), 6.45 (t, J=8.8 Hz, 1H), 6.34 (t, J=9.2 Hz, 1H), 4.67 (s, 2H).
92%	With hydrogen In methanol for 2 h;	A solution of l-benzyloxy-2,3-difluoro-4-nitrobenzene (14 g, 52.8 mmol) in MeOH (200 mL) was stirred with Pd/C (10percent, 1.4 g, 1.3 mmol) under a hydrogen atmosphere (30 psi) for 2 h. The catalyst was removed by filtration, and the filtrate was concentrated in vacuo to afford 4-amino-2,3-difluorophenol (7 g, 92percent yield). ¹H NMR (400 MHz, DMSO-d₆): δ 9.05 (s, 1 H), 6.45 (t, J= 8.8 Hz, 1 H), 6.34 (t, J= 9.2 Hz, 1 H), 4.67 (s, 2 H); MS (ESI) m/z: 146.1[M+H]⁺.
92%	With palladium 10% on activated carbon; hydrogen In methanol for 2 h;	A mixture of l-benzyloxy-2,3-difluoro-4-nitrobenzene (14 g, 52.8 mmol) and Pd/C (10percent, 1.4 g) in MeOH (200 mL) was stirred under a hydrogen atmosphere (30 psi) for 2 h. The catalyst was removed by filtration and the filtrate was concentrated in vacuo to afford 4-amino-2,3difiuoro-phenol (7 g, 92percent yield). 1H NMR (400 MHz, DMSO-i/₆) δ 9.05 (s, 1 H), 6.45 (t, J= 8.8 Hz, 1 H), 6.34 (t, J= 9.2 Hz, 1 H), 4.67 (s, 2 H).

84%	With palladium 10% on activated carbon In tetrahydrofuran; methanol at 32℃; for 13 h;	To a suspension of 1 -(benzyl oxy)-2,3-difluoro-4-nitrobenzene (1.93 g, 0.73 mmol) in CH₃OH (45 mL) and THF (9 mL) was added Pd/C (333 mg, 10percent). The reaction was stirred at 32 °C for 13 hours under atmosphere, and then filtered through a CELITE^® pad. The filtrate was extracted with EtOAc (30 mL). The organic phase was washed with water (30 mL), dried over Na₂S0₄ and concentrated in vacuo. The residue was stirred in CH2CI2 (4 mL) for 2 hours and then collected through filtration to give the title compound as a dark brown solid (0.89 g, 84percent). MS (ESI, pos. ion) m/z: 146.2 [M+H]⁺; NMR (400 MHz, DMSO-i): δ 6.49 (m, 1H), 6.38 (m, 1H), 4.71 (s, 2H).
84%	With 5% Pd/C; hydrogen In tetrahydrofuran; methanol; water at 32℃; for 13 h;	Step 2) 4-amino-2,3-difluorophenol [0177] To a suspension of 1 -(benzyl oxy)-2,3-difluoro-4-nitrobenzene (1.93 g, 0.73 mmol) in CH₃OH (45 mL) and THF (9 mL) was added Pd/C (333 mg, 6percent Pd content, 53 percent ~ 55 percent water content). The mixture was stirred at 32 °C for 13 hours under H₂ atmosphere. The mixture was filtered through a CELITE^® pad, which was washed with 50 mL of EtOAc. The filtrate was concentrated in vacuo, washed with 30 mL of CH2CI2 to give the title compound as a dark brown solid (0.89 g, 84 percent). MS (ESI, pos. ion) m/z: 146.2 [M+H]⁺; NMR (400 MHz, DMSO-i): δ (ppm) 6.49 (m, 1H), 6.38 (m, 1H), 4.71 (s, 2H).
84%	With 5% Pd/C; hydrogen In tetrahydrofuran; methanol; water at 32℃; for 13 h;	Step 2) 4-amino-2,3-difluorophenol To a suspension of 1-(benzyloxy)-2,3-difluoro-4-nitrobenzene (1.93 g, 0.73 mmol) in CH₃OH (45 mL) and THF (9 mL) was added Pd/C (333 mg, 6percent Pd content, 53percent˜55percent water content). The mixture was stirred at 32° C. for 13 hours under H₂ atmosphere. The mixture was filtered through a CELITE® pad, which was washed with 50 mL of EtOAc. The filtrate was concentrated in vacuo, washed with 30 mL of CH₂Cl₂ to give the title compound as a dark brown solid (0.89 g, 84percent). MS (ESI, pos. ion) m/z: 146.2 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) 6.49 (m, 1H), 6.38 (m, 1H), 4.71 (s, 2H).

Reference： [1] Patent: US2008/90856, 2008, A1, . Location in patent: Page/Page column 41
[2] Patent: WO2010/51373, 2010, A1, . Location in patent: Page/Page column 61
[3] Patent: WO2013/36232, 2013, A2, . Location in patent: Paragraph 00279
[4] Patent: WO2013/180949, 2013, A1, . Location in patent: Paragraph 0180
[5] Patent: WO2014/22116, 2014, A2, . Location in patent: Paragraph 0177
[6] Patent: US2015/37280, 2015, A1, . Location in patent: Paragraph 0303-0305

2
[ 441713-58-2 ]
[ 868735-81-3 ]
[ 115551-33-2 ]
[ 163733-99-1 ]

Reference： [1] Patent: US2005/245530, 2005, A1, . Location in patent: Page/Page column 93
[2] Patent: EP1889836, 2008, A1, . Location in patent: Page/Page column 86

3
[ 847872-04-2 ]
[ 163733-99-1 ]

Reference： [1] Patent: EP1514865, 2005, A1, . Location in patent: Page/Page column 9

4
[ 771-69-7 ]
[ 163733-99-1 ]

Reference： [1] Patent: WO2013/36232, 2013, A2,
[2] Patent: WO2013/180949, 2013, A1,
[3] Patent: WO2014/22116, 2014, A2,

5
[ 2105-61-5 ]
[ 163733-99-1 ]

Reference： [1] Patent: US2015/37280, 2015, A1,

[ 163733-99-1 ] Synthesis Path-Downstream 1~32

1
[ 99586-65-9 ]
[ 163733-99-1 ]
[ 868735-84-6 ]
[ 868735-85-7 ]

Yield	Reaction Conditions	Operation in experiment
		(Production Example 112) 4-(4-Amino-2,3-diflurophenoxy)pyridine-2-carboxamide The mixture of 4-amino-2,3-difluorophenol and 6-amino-2,3-difluorophenol (3.52 g) was dissolved in dimethyl sulfoxide (30 ml) under a nitrogen flow, and potassium tert-butoxide (1.49 g) was added at room temperature, followed by stirring for 30 min. 4-Chloropyridine-2-carboxamide (947 mg) was added thereto, followed by stirring at 80 C for 6 hr. Then the reaction mixture was stirred at 100C for 14hr. The reaction mixture was allowed to cool down to room temperature, and a 1N aqueous solution of sodium hydroxide (52.8 ml) was added, followed by stirring for 9 hr and 15 min. The reaction mixture was partitioned between ethyl acetate (300 ml) and water (300 ml). The aqueous layer was extracted with ethyl acetate (200 ml, twice), then the combined organic layer was dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; heptane:ethyl acetate = 1:3) and fractions containing the target compound were concentrated under reduced pressure. The residue was dried under reduced pressure to provide the titled compound as a pale brown solid (532 mg) which was a mixture of 4-(6-amino-2,3-diflurophenoxy)pyridine-2-carboxamide.

Reference： [1]Patent: EP1889836,2008,A1 .Location in patent: Page/Page column 86

2
[ 868735-81-3 ]
[ 163733-99-1 ]

Yield	Reaction Conditions	Operation in experiment
92%	With hydrogen;palladium 10% on activated carbon; In methanol; under 1551.49 Torr; for 2h;	A mixture of 1-benzyloxy-2,3-difluoro-4-nitrobenzene (14 g, 52.8 mmol) and Pd/C (10%, 1.4 g) in MeOH (200 mL) was stirred under a hydrogen atmosphere (30 psi) for 2 h. The catalyst was removed by filtration and the filtrate was concentrated in vacuo to afford 4-amino-2,3difluoro-phenol (7 g, 92% yield). 1H NMR (400 MHz, DMSO-d6) delta 9.05 (s, 1H), 6.45 (t, J=8.8 Hz, 1H), 6.34 (t, J=9.2 Hz, 1H), 4.67 (s, 2H).
92%	With hydrogen;palladium 10% on activated carbon; In methanol; under 1551.49 Torr; for 2h;	A solution of l-benzyloxy-2,3-difluoro-4-nitrobenzene (14 g, 52.8 mmol) in MeOH (200 mL) was stirred with Pd/C (10%, 1.4 g, 1.3 mmol) under a hydrogen atmosphere (30 psi) for 2 h. The catalyst was removed by filtration, and the filtrate was concentrated in vacuo to afford 4-amino-2,3-difluorophenol (7 g, 92% yield). 1H NMR (400 MHz, DMSO-d6): delta 9.05 (s, 1 H), 6.45 (t, J= 8.8 Hz, 1 H), 6.34 (t, J= 9.2 Hz, 1 H), 4.67 (s, 2 H); MS (ESI) m/z: 146.1[M+H]+.
92%	With palladium 10% on activated carbon; hydrogen; In methanol; for 2h;	A mixture of l-benzyloxy-2,3-difluoro-4-nitrobenzene (14 g, 52.8 mmol) and Pd/C (10%, 1.4 g) in MeOH (200 mL) was stirred under a hydrogen atmosphere (30 psi) for 2 h. The catalyst was removed by filtration and the filtrate was concentrated in vacuo to afford 4-amino-2,3difiuoro-phenol (7 g, 92% yield). 1H NMR (400 MHz, DMSO-i/6) delta 9.05 (s, 1 H), 6.45 (t, J= 8.8 Hz, 1 H), 6.34 (t, J= 9.2 Hz, 1 H), 4.67 (s, 2 H).

84%	With palladium 10% on activated carbon; In tetrahydrofuran; methanol; at 32℃; for 13h;	To a suspension of 1 -(benzyl oxy)-2,3-difluoro-4-nitrobenzene (1.93 g, 0.73 mmol) in CH3OH (45 mL) and THF (9 mL) was added Pd/C (333 mg, 10%). The reaction was stirred at 32 C for 13 hours under atmosphere, and then filtered through a CELITE pad. The filtrate was extracted with EtOAc (30 mL). The organic phase was washed with water (30 mL), dried over Na2S04 and concentrated in vacuo. The residue was stirred in CH2CI2 (4 mL) for 2 hours and then collected through filtration to give the title compound as a dark brown solid (0.89 g, 84%). MS (ESI, pos. ion) m/z: 146.2 [M+H]+; NMR (400 MHz, DMSO-i): delta 6.49 (m, 1H), 6.38 (m, 1H), 4.71 (s, 2H).
84%	With 5% Pd/C; hydrogen; In tetrahydrofuran; methanol; water; at 32℃; for 13h;	Step 2) 4-amino-2,3-difluorophenol [0177] To a suspension of 1 -(benzyl oxy)-2,3-difluoro-4-nitrobenzene (1.93 g, 0.73 mmol) in CH3OH (45 mL) and THF (9 mL) was added Pd/C (333 mg, 6% Pd content, 53 % ~ 55 % water content). The mixture was stirred at 32 C for 13 hours under H2 atmosphere. The mixture was filtered through a CELITE pad, which was washed with 50 mL of EtOAc. The filtrate was concentrated in vacuo, washed with 30 mL of CH2CI2 to give the title compound as a dark brown solid (0.89 g, 84 %). MS (ESI, pos. ion) m/z: 146.2 [M+H]+; NMR (400 MHz, DMSO-i): delta (ppm) 6.49 (m, 1H), 6.38 (m, 1H), 4.71 (s, 2H).
84%	With 5% Pd/C; hydrogen; In tetrahydrofuran; methanol; water; at 32℃; for 13h;	Step 2) 4-amino-2,3-difluorophenol To a suspension of 1-(benzyloxy)-2,3-difluoro-4-nitrobenzene (1.93 g, 0.73 mmol) in CH3OH (45 mL) and THF (9 mL) was added Pd/C (333 mg, 6% Pd content, 53%?55% water content). The mixture was stirred at 32 C. for 13 hours under H2 atmosphere. The mixture was filtered through a CELITE pad, which was washed with 50 mL of EtOAc. The filtrate was concentrated in vacuo, washed with 30 mL of CH2Cl2 to give the title compound as a dark brown solid (0.89 g, 84%). MS (ESI, pos. ion) m/z: 146.2 [M+H]+; 1H NMR (400 MHz, DMSO-d6): delta (ppm) 6.49 (m, 1H), 6.38 (m, 1H), 4.71 (s, 2H).

Reference： [1]Patent: US2008/90856,2008,A1 .Location in patent: Page/Page column 41
[2]Patent: WO2010/51373,2010,A1 .Location in patent: Page/Page column 61
[3]Patent: WO2013/36232,2013,A2 .Location in patent: Paragraph 00279
[4]Patent: WO2013/180949,2013,A1 .Location in patent: Paragraph 0180
[5]Patent: WO2014/22116,2014,A2 .Location in patent: Paragraph 0177
[6]Patent: US2015/37280,2015,A1 .Location in patent: Paragraph 0303-0305

3
[ 847872-04-2 ]
[ 163733-99-1 ]

Reference： [1]Patent: EP1514865,2005,A1 .Location in patent: Page/Page column 9

4
[ 441713-58-2 ]
[ 868735-81-3 ]
[ 115551-33-2 ]
[ 163733-99-1 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogen;palladium 10% on activated carbon; In methanol; ethyl acetate; for 12h;	To a solution of 1,2,3-trifluoro-4-nitrobenzene (Aldrich, 15.0 g, 84.7 mmol) in DMF (25.0 mL) were added K2CO3 (17.6 g, 127.8 mmol) and benzylalcohol (8.8 mL, 85.0 mmol). The suspension was stirred overnight. To the reaction mixture was then added H2O (100 mL) and the solution was kept at 4 C. overnight. The precipitate was then collected and washed with H2O to give a mixture of two isomers (22.4 g) [1-(benzyloxy)-2,3-difluoro-4-nitrobenzene and 2-(benzyloxy)-3,4-difluoro-1-nitrobenzene in a ratio of 1: 1]. To a solution of [1-(benzyloxy)-2,3-difluoro-4-nitrobenzene and 2-(benzyloxy)-3,4-difluoro-1-nitrobenzene] (22.4 g, 84.5 mmol) in EtOAc (20.0 mL) and MeOH (100.0 mL) was added 10% Pd/C (1.0 g). The suspension was stirred under H2 atmosphere for 12 h. The suspension was then filtered and concentrated in vacuo to give a mixture of two isomers (12.6 g) [4-amino-2,3-difluorophenol and 6-amino-2,3-difluorophenol in a ratio of 1:1]. MS (ESI+): m/z 146.00 (M+H)+.
	With hydrogen;palladium 10% on activated carbon; In methanol; at 20℃; for 26.8333h;	(Production Example 111) 4-Amino-2,3-difluorophenol To a solution of a mixture of 1-(benzyloxy)-2,3-difluoro-4-nitrobenzene and 2-(benzyloxy)-3,4-difluoro-1-nitrobenzene (6.54 g) in methanol (200 ml) was added 10 % palladium on carbon (654 mg), followed by stirring under a hydrogen atmosphere at room temperature for 26 hr and 50 min. The atmosphere in the reaction vessel was replaced with nitrogen to stop the reaction, and the catalyst was filtered off through Celite. The filtrate was concentrated under reduced pressure to provide the titled compound as a black solid (3.52 g) which was a mixture of 6-amino-2,3-difluorophenol.

Reference： [1]Patent: US2005/245530,2005,A1 .Location in patent: Page/Page column 93
[2]Patent: EP1889836,2008,A1 .Location in patent: Page/Page column 86

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 10 At room temperature, 3.5 g (0.015 mol) of (2,3-difluoro-4-hydroxyphenyl)-phenyldiazene are dissolved in 30 ml of methanol in a 100 ml three-neck flask fitted with internal thermometer, stirrer and gas inlet tube. The flask is flushed with argon, and 1.5 g of Raney nickel and 25 mul of bis(2-hydroxyethyl) sulphide are then added. 692 ml of hydrogen (0.03 mol) are then applied at room temperature with a pressure of about 1 bar. The reaction mixture is admixed with activated charcoal, stirred for a further 15 minutes and filtered over a bed of silica gel. The solvent is distilled off and the residue is washed with n-hexane, affording 2.0 g (91.9% of theory) of 4-hydroxy-2,3-difluoroaniline.

6
[ 26452-80-2 ]
[ 163733-99-1 ]
[ 1020173-30-1 ]

Yield	Reaction Conditions	Operation in experiment
66%		<strong>[163733-99-1]4-amino-2,3-difluorophenol</strong> (6 g, 41.4 mmol) and potassium tert-butoxide (4.9 g, 43.5 mmol) were suspended in DMAc (200 mL) and stirred at RT for 30 min under Ar atmosphere. 2,4-Dichloropyridine (6.1 g, 41.4 mmol) was added, and the resulting mixture was heated to 70 C for 8 h. The reaction mixture was filtered, concentrated in vacuo and purified by silica gel chromatography to afford 4-(2- chloro-pyridin-4-yloxy)-2,3-difluoro-phenylamine (7 g, 66% yield). 1H NMR (400 MHz, DMSO-d6): delta 8.27 (d, J= 6.0 Hz, 1 H), 7.05 (s, 1 H), 6.95 (m, 1 H), 6.92 (m, 1 H), 6.62 (m, 1 H), 5.60 (s, 2 H); MS (ESI) m/z: 257.1[M+H]+.

Reference： [1]Patent: WO2010/51373,2010,A1 .Location in patent: Page/Page column 61

7
[ 1123838-02-7 ]
potassium tart-butoxide [ No CAS ]
[ 163733-99-1 ]
[ 1341215-98-2 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium chloride; In dimethyl sulfoxide; ethyl acetate;	Step 1. tert-butyl (6-(7-(4-amino-2,3-difluorophenoxy)thieno[3,2-b]pyridin-2-yl)pyridin-3-yl)methyl(2-methoxyethyl)carbamate (23) To a stirred solution of <strong>[163733-99-1]4-amino-2,3-difluorophenol</strong> (1.471 g, 10.14 mmol) in DMSO (11.5 mL) at RT under nitrogen was added potassium tart-butoxide (1.345 g, 11.98 mmol). After 30 min, tert-butyl (6-(7-chlorothieno[3,2-b]pyridin-2-yl)pyridin-3-yl)methyl(2-methoxyethyl)carbamate (22, 4.0 g, 9.22 mmol) was added and the reaction mixture was heated at 100 C. for 2.5 h, then cooled to RT. The reaction mixture was poured into water (90 mL) and stirred for 30 min. A saturated aqueous solution of sodium chloride was added and the mixture was stirred at RT for 3 days. The solid was collected by filtration, rinsed with water, air-dried and dried under high vacuum. The crude product was purified by Biotage (40+M cartridge; AcOEt/hexanes:50/50 over 3 CV, 50/50 to 100% AcOEt over 6 CV, then 100% AcOEt over 8 CV), to provide a material that upon trituration with diethyl ether afforded title compound 23 (1.94 g, 3.58 mmol, 38% yield) as an off-white solid. MS (m/z): 543.3 (M+H).

Reference： [1]Patent: US2011/257100,2011,A1

8
[ 1123838-17-4 ]
[ 163733-99-1 ]
[ 1342836-68-3 ]

Yield	Reaction Conditions	Operation in experiment
79%	With potassium tert-butylate; In dimethyl sulfoxide;	Step 3: 4-(2-(5-(1,3-Dioxolan-2-yl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)-2,3-difluoroaniline (302) To a solution of <strong>[163733-99-1]4-amino-2,3-difluorophenol</strong> (1.59 g, 7.49 mmol) in DMSO (10 mL) was added potassium tert-butoxide (1.1 g, 8.98 mmol), and the reaction mixture was stirred for 2 hours. Chloride 301 (1.6 g, 4.99 mmol) was added and the reaction mixture was heated at 100 C. for 2 hours. The mixture was cooled down then poured into water (150 mL) at 40-45 C. and stirred for 30 min. The precipitate was collected by filtration, washed with water and dried overnight. The crude product was triturated with EtOAc/Hexane (2/1, 100 mL) for 1 h, to afford title compound 302 (1.7 g, 79% yield) as a pale violet solid. 1H NMR (300 MHz, DMSO-d6) delta (ppm): 8.70 (d, J=2.1 Hz, 1H), 8.53 (d, J=5.4 Hz, 1H), 8.39 (s, 1H), 8.31 (d, J=8.1 Hz, 1H), 7.98 (dd, J=8.1, 2.1 Hz, 1H), 7.10-7.00 (m, 1H), 6.71 (d, J=5.1 Hz, 1H), 6.72-6.61 (m, 1H), 5.90 (s, 1H), 5.64 (s, 2H), 4.16-3.96 (m, 4H).

Reference： [1]Patent: US2011/257100,2011,A1

9
[ 1123838-02-7 ]
[ 163733-99-1 ]
[ 1341215-98-2 ]

Yield	Reaction Conditions	Operation in experiment
38%		To a stirred solution of <strong>[163733-99-1]4-amino-2,3-difluorophenol</strong> (1 .471 g, 10.14 mmol) in DMSO (1 1.5 mL) at RT under nitrogen was added potassium r/-butoxide (1.345 g, 1 1.98 mmol). After 30 min, compound 66 (4.0 g, 9.22 mmol, scheme 12) was added and the reaction mixture was heated at 100C for 2.5 h then cooled to RT. The reaction mixture was poured into water (90 mL) and stirred for 30 min. A saturated aqueous solution of sodium chloride was added and the mixture was stirred at RT for 3 days. The solid was collected by filtration, rinsed with water and dried. The crude product was purified by Biotage (40+M cartridge; AcOEt/hexanes: 50/50 over 3 CV, 50/50 to 100% AcOEt over 6 CV, then 100% AcOEt over 8 CV), to provide a material that upon trituration with diethyl ether afforded title compound 103 (1.94 g, 3.58 mmol, 38% yield) as an off-white solid. MS (m/z): 543.3 (M+H).

Reference： [1]Patent: WO2013/44360,2013,A1 .Location in patent: Paragraph 000312

10
[ 666734-51-6 ]
[ 163733-99-1 ]
[ 1437323-99-3 ]

Yield	Reaction Conditions	Operation in experiment
18%		Potassium tert-butoxide (0.13 g, 1.12 mmol) was added to 4-amino-2-fluorophenol in dry N-methylpyrrolidinone (5 mL, 50 mmol) at rt and stirred for 30 min under an atmosphere of nitrogen . Then solid <strong>[666734-51-6]4-bromo-6,7-dimethoxyquinoline</strong> (0.30 g, 1.1 mmol) was added and the reaction stirred at 100 °C for 30 h. The mixture was concentrated, dissolved in EtOAc (-75 mL), and washed lx with IN Na2C03, water and NaCl solution, then dried over MgSC^. The product was chromatographed on silica gel (5percent MeOH/DCM) to give 4-(6,7-dimethoxyquinolin-4-yloxy)-2,3-difluoro-phenylamine 0.066 g (18percent). LCMS m/z = 333 (M + 1). 1H NMR (CDC13) ?: 8.5 (d, 1H, J = 8 Hz), 7.58 (s, 1H), 7.44 (s, 1H), 6.89-6.83 (m, 1H), 6.64-6.58 (m, 1H), 6.42 (d, 1H, J = 5 Hz), 4.05 (d, 6H, J = 5 Hz).

Reference： [1]Patent: WO2013/74633,2013,A1 .Location in patent: Page/Page column 121-122

11
[ 771-69-7 ]
[ 163733-99-1 ]

Reference： [1]Patent: WO2013/36232,2013,A2
[2]Patent: WO2013/180949,2013,A1
[3]Patent: WO2014/22116,2014,A2

12
[ 68500-37-8 ]
[ 163733-99-1 ]
2,3-difluoro-4-((7-methoxyquinolin-4-yl)oxy)aniline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
25.4%		To a solution of 4-amino-2,3-difluorophenol (208 mg, 1.43 mmol) in DMF (4 mL) was added i-BuOK (257 mg, 2.29 mmol). The mixture was stirred at rt for 30 minutes, followed by the addition of <strong>[68500-37-8]4-chloro-7-methoxyquinoline</strong> (308 mg, 1.59 mmol). The reaction was microwaved at 120 °C for 2 hours, then cooled to rt, quenched with 25 mL of water and extracted with EtOAc (30 mL x 3). The combined organic phases were washed with brine (30 mL x 3), dried over Na2S04 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 1/2) to give the title compound as a pale yellow solid (110 mg, 25.4percent). MS (ESI, pos. ion) m/z: 303.2 [M+H]+; FontWeight="Bold" FontSize="10" H NMR (400 MHz, DMSO-i): delta 8.60 (d, J= 5.2 Hz, 1H), 8.21 (d, J= 9.2 Hz, 1H), 7.40 (d, J= 2.4 Hz, 1H), 7.29 (dd, J= 2.4 Hz, 9.2 Hz, 1H), 6.99 (m, 1H), 6.66 (m, 1H ), 6.48 (d, J= 5.0 Hz, 1H), 5.60 (s, 2H), 3.93 (s, 3H).

Reference： [1]Patent: WO2013/180949,2013,A1 .Location in patent: Paragraph 0181

13
[ 163733-99-1 ]
N-(2,3-difluoro-4-((7-methoxyquinolin-4-yl)oxy)phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide [ No CAS ]

Reference： [1]Patent: WO2013/180949,2013,A1

14
[ 35654-56-9 ]
[ 163733-99-1 ]
[ 1437323-99-3 ]

Yield	Reaction Conditions	Operation in experiment
15.8%		To a solution of <strong>[163733-99-1]4-amino-2,3-difluorophenol</strong> (208 mg, 1.43 mmol) in DMF (4 mL) was added /-BuOK (257 mg, 2.29 mmol). The mixture was stirred at rt for 30 minutes, followed by the addition of 4-chloro-6,7-dimethoxyquinoline (356 mg, 1.59 mmol). The reaction was heated at 120 C for 2 hours in microwave, then cooled to rt, quenched with water (25 mL), and extracted with EtOAC (30 mL x 3). The combined organic phases were washed with brine (30 mL x 3), dried over Na2S04 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 1/3) to give the title compound as a pale yellow solid (75 mg, 15.8%). MS (ESI, pos. ion) m/z: 333.2 [M+H]+; *H NMR (400 MHz, DMSO-i): delta 8.47 (d, J = 5.1 Hz, 1H), 7.51 (s, 1H), 7.40 (s, 1H), 6.99 (m, 1H), 6.76 (m, 1H ), 6.47 (d, J= 4.9 Hz, 1H), 5.90 (s, 2H), 3.94 (s, 6H).

Reference： [1]Patent: WO2013/180949,2013,A1 .Location in patent: Paragraph 0188

15
[ 35654-56-9 ]
[ 163733-99-1 ]
N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-2,3-difluorophenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide [ No CAS ]

Reference： [1]Patent: WO2013/180949,2013,A1

16
[ 99586-65-9 ]
[ 163733-99-1 ]
[ 868735-84-6 ]

Yield	Reaction Conditions	Operation in experiment
41.5%		Step 3) 4-(4-amino-2,3-difluorophenoxy)picolinamide [0178] To a solution of 4-amino-2,3-difluorophenol (208 mg, 1.43 mmol) in DMF (4 mL) was added i-BuOK (257 mg, 2.29 mmol). The reaction was stirred at rt for 30 minutes, then <strong>[99586-65-9]4-chloropicolinamide</strong> (249 mg, 1.59 mmol) was added. The mixture was microwaved at 120 C for 3 hours, then cooled to rt and diluted with 25 mL of water. The resulted mixture was extracted with EtOAc (30 mL x 3), and the combined organic phases were washed with brine (30 mL x 3), dried over anhydrous a2S04, and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 1/2) to give the title compound as an orange solid (110 mg, 41.5 %). MS (ESI, pos. ion) m/z: 266.0 [M+H]+, 283.2 [M+NH4] +; FontWeight="Bold" FontSize="10" H NMR (400 MHz, DMSO-i): delta (ppm) 8.42 (d, J= 5.6 Hz, 1H), 7.84 (br s, 1H), 7.65 (d, J= 2.5 Hz, 1H ), 7.03 (m, 1H), 6.77 (m, 1H), 6.56 (m, 1H), 5.56 (br s, 1H), 3.08 (s, 2H).
41.5%		Step 3) 4-(4-amino-2,3-difluorophenoxy)picolinamide To a solution of 4-amino-2,3-difluorophenol (208 mg, 1.43 mmol) in DMF (4 mL) was added t-BuOK (257 mg, 2.29 mmol). The reaction was stirred at rt for 30 minutes, then <strong>[99586-65-9]4-chloropicolinamide</strong> (249 mg, 1.59 mmol) was added. The mixture was microwaved at 120 C. for 3 hours, then cooled to rt and diluted with 25 mL of water. The resulted mixture was extracted with EtOAc (30 mL3), and the combined organic phases were washed with brine (30 mL3), dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v)=1/2) to give the title compound as an orange solid (110 mg, 41.5%). MS (ESI, pos. ion) m/z: 266.0 [M+H]+, 283.2 [M+NH4]+; 1H NMR (400 MHz, DMSO-d6): delta (ppm) 8.42 (d, J=5.6 Hz, 1H), 7.84 (br s, 1H), 7.65 (d, J=2.5 Hz, 1H), 7.03 (m, 1H), 6.77 (m, 1H), 6.56 (m, 1H), 5.56 (br s, 1H), 3.08 (s, 2H).

Reference： [1]Patent: WO2014/22116,2014,A2 .Location in patent: Paragraph 0178
[2]Patent: US2015/37280,2015,A1 .Location in patent: Paragraph 0306-0308

17
[ 3934-20-1 ]
[ 163733-99-1 ]
[ 1562519-47-4 ]

Yield	Reaction Conditions	Operation in experiment
4.827 g	With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 0 - 20℃; for 2h;	Intermediate G5: 4-((2-Chloropyri difluoroaniline DBU (7.27 ml, 48.2 mmol) was added over 5 min to a stirred mixture of 4-amino-2,3- difluorophenol (5 g, 34.5 mmol) in MeCN (100 mL) at 0-5C. After stirring for 5 min, 2,4- dichloropyrimidine (5.49 g, 36.9 mmol) was added portionwise over 5 min then the mixture warmed to rt and stirred for 2h. The solvent was evaporated under reduced pressure and the residue partitioned between ether (200 mL) and water (200 mL). The aqueous layer was extracted with ether (200 mL) then the combined organic layers washed with brine (200 mL), dried (MgS04) and evaporated under reduced pressure. The crude product was purified by chromatography on silica gel (120 g column, 0-40% EtOAc/isohexane) to afford Intermediate G5 (4.827 g) as a solid. 1H NMR (400MHz; CDCI3) delta 8.46 (d, 1 H), 6.89 (d, 1 H), 6.81-6.77 (m, 1 H), 6.58-6.53 (m, 1 H), 3.85 (s, 2H). LCMS m/z 258/260 (M+H)+ (ES+)
4.827 g	With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 0 - 20℃; for 2h;	(i) 4-((2-Chloropyrimidin-4-yl)oxy)-2,3-difluoroaniline DBU (7.27 mL, 48.2 mmol) was added over 5min to a stirred mixture of 4-amino-2,3- difluorophenol (5 g, 34.5 mmol) in MeCN (100 mL) at 0-5C. After stirring for 5min, 2,4- dichloropyrimidine (5.49 g, 36.9 mmol) was added portionwise over 5 min then the mixture warmed to rt and stirred for 2h. The solvent was evaporated under reduced pressure and the residue partitioned between ether (200 mL) and water (200 mL). The aqueous layer was extracted with ether (200 mL) then the combined organic layers washed with brine (200 mL), dried (MgS04) and evaporated under reduced pressure. The crude product was purified by chromatography on silica gel (120 g column, 0-40% EtOAc/isohexane) to afford the sub-title compound (4.827 g) as a solid. 1 H NMR (400MHz; CDCI3) delta 8.46 (d, 1 H), 6.89 (d, 1 H), 6.81-6.77 (m, 1 H), 6.58-6.53 (m, 1 H), 3.85 (s, 2H). LCMS m/z 258/260 (M+H)+ (ES+)

Reference： [1]Patent: WO2014/27209,2014,A1 .Location in patent: Page/Page column 91-92
[2]Patent: WO2014/76484,2014,A1 .Location in patent: Page/Page column 67

18
[ 163733-99-1 ]
[ 1562518-45-9 ]

Reference： [1]Patent: WO2014/27209,2014,A1
[2]Patent: WO2014/76484,2014,A1

19
[ 163733-99-1 ]
[ 1610449-47-2 ]

Reference： [1]Patent: WO2014/76484,2014,A1

20
[ 2105-61-5 ]
[ 163733-99-1 ]

Reference： [1]Patent: US2015/37280,2015,A1

21
[ 99586-65-9 ]
[ 163733-99-1 ]
[ 1552280-92-8 ]

Reference： [1]Patent: US2015/37280,2015,A1

22
[ 163733-99-1 ]
[ 928038-51-1 ]

Reference： [1]Patent: EP1889836,2008,A1

23
[ 163733-99-1 ]
N-[4-({2-[({3-[(Dimethylamino)methyl]azetidine-1-yl}carbonyl)amino]pyridin-4-yl}oxy)-2,3-difluorophenyl]-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide [ No CAS ]

Reference： [1]Patent: EP1889836,2008,A1

24
[ 163733-99-1 ]
N-{2,3-difluoro-4-[(2-[(3-hydroxyazetidin-1-yl)carbonyl]amino}pyridin-4-yl)oxy]phenyl}-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide [ No CAS ]

Reference： [1]Patent: EP1889836,2008,A1

25
[ 163733-99-1 ]
[ 928038-50-0 ]

Reference： [1]Patent: EP1889836,2008,A1

26
4,6-dichloro-3-(trifluoromethyl)-1-[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine [ No CAS ]
[ 163733-99-1 ]
4-[6-chloro-3-(trifluoromethyl)-1-[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}-2,3-difluoroaniline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In dimethyl sulfoxide; at 120℃; for 3h;	A mixture of 4,6-dichloro-3-(trifluoromethyl)-1 -[2-(trimethylsilyl)ethoxy]methyl}-1 H-pyrrolo[2,3- b]pyridine (500 mg, 1 .30 mmol, intermediate 66), commercially available 4-amino-2,3- difluorophenol (207 mg, 1 .43 mmol) and potasium carbonate (538 mg, 3.89 mmol) in 5.0 mL DMSO was stirred at 120C for 3h. After cooling to room temperature this mixture was diluted with 200 mL ethyl acetate. The resulting organic phase was then extracted twotimes with 30 mL of water, 20 mL brime, dried over sodium sulfate, filtered and evaporated to dryness. The residue was purified using a Biotage chromatography system to obtain 170 mg (93 % purity, 25% yield) of the desired title compound. 1H-NMR (400 MHz, DMSO-d6) delta [ppm]: -0.1 1 - -0.07 (m, 9H), 0.81 - 0.88 (m, 2H), 3.54 - 3.61 (m, 2H), 5.62 (s, 2H), 5.65 (s, 2H), 6.51 (s, 1 H), 6.65 (td, 1 H), 6.99 (td, 1 H), 8.38 (s, 1 H).

Reference： [1]Patent: WO2018/228920,2018,A1 .Location in patent: Page/Page column 132

27
tert-butyl ((1r,4r)-4-((4-(2-fluoropyridin-3-yl)pyrimidin-2-yl)amino)cyclohexyl)carbamate [ No CAS ]
[ 163733-99-1 ]
C₂₆H₃₀F₂N₆O₃ [ No CAS ]

Reference： [1]ACS Chemical Biology,2019,vol. 14,p. 2595 - 2605

28
(S)-tert-butyl 3-((4-(2-fluoropyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate [ No CAS ]
[ 163733-99-1 ]
tert-butyl (3S)-3-[[4-[2-(4-amino-2,3-difluoro-phenoxy)-3-pyridyl]pyrimidin-2-yl]amino]piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
83.9%	With caesium carbonate; In dimethyl sulfoxide; at 130℃; for 6h;	A solution of 4-ammo-2,3 -difluoro-phenol (1.94 g . 13.4 mmol), it?ri-butyl ( 3.S)_3_ ((4-(2-fluoro-3-pyridyl)pyrimidin-2-yl)amino)piperidine-l-carboxylate (5.00 g, 13.4 mmol) and cesium carbonate (7.42 g, 22.8 mmol) in DMSO (45 mL) was stirred at 130 C for 6 h. LCMS showed complete conversion. The resulting solution was diluted with water and extracted with ethyl acetate. The organic layers were washed twice with brine and dried over anhydrous sodium sulfate. The solvent was concentrated under vacuum. The residue was purified by silica flash chromatography eluting with ethyl acetate/petroleum ether (20%-50%) to afford the title compound (5.60 g, 83.9% yield) as a black solid. LCMS (ESI): [M+H]+ = 499.2.

Reference： [1]Patent: WO2020/56089,2020,A1 .Location in patent: Paragraph 0386

29
[ 108-24-7 ]
[ 163733-99-1 ]
(4-amino-2,3-difluoro-phenyl) acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
64%	With pyridine; at 0 - 20℃; for 16h;	To a solution of <strong>[163733-99-1]4-amino-2,3-difluoro-phenol</strong> (4.0 g, 27.6 mmol) in pyridine (50 mL) was added acetic anhydride (2.59 mL, 27.6 mmol) at 0 C and the mixture was stirred for l6h at room temperature. The mixture was concentrated and purified by silica flash chromatography (ethyl acetate/petroleum ether 0-100%) to afford the title compound (3.3 g, 64% yield) as a brown solid.

Reference： [1]Patent: WO2020/56089,2020,A1 .Location in patent: Paragraph 0410

30
benzyl (3S,5R)-3-((4-(2-fluoropyridin-3-yl)pyrimidin-2-yl)amino)-5-methylpiperidine-1-carboxylate [ No CAS ]
[ 163733-99-1 ]
benzyl (3S,5R)-3-((4-(2-(4-amino-2,3-difluorophenoxy)pyridin-3-yl)pyrimidin-2-yl)amino)-5-methylpiperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
43%	With caesium carbonate; In dimethyl sulfoxide; at 130℃; for 1.5h;Inert atmosphere;	A mixture of benzyl (3ri',5i?)-3-((4-(2-fluoropyridin-3-yl)pyrimidin-2-yl)amino)-5- methylpiperidine-l-carboxylate (1 g, 2.37 mmol), <strong>[163733-99-1]4-amino-2,3-difluorophenol</strong> (344 mg, 2.37 mmol), cesium carbonate (928 mg, 2.85 mmol) in DMSO (20 mL) was degassed and purged with N2 3 times. The mixture was stirred at 130 C for 1.5 h under N2 atmosphere and then cooled to room temperature. Water was added, and the mixture was then extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na^SCh. filtered and concentrated in vacuo. The residue was purified by silica column chromatography (0657) (petroleum ether/ethyl acetate=20/l to 1 : 1) to provide the title compound (3.9 g, 43% yield) as a brown solid.

Reference： [1]Patent: WO2020/56089,2020,A1 .Location in patent: Paragraph 0327

31
[ 163733-99-1 ]
(4-amino-5-bromo-2,3-difluoro-phenyl) acetate [ No CAS ]

Reference： [1]Patent: WO2020/56089,2020,A1

32
[ 163733-99-1 ]
tert-butyl acetyl(6-bromo-2,3-difluoro-4-hydroxyphenyl)carbamate [ No CAS ]

Reference： [1]Patent: WO2020/56089,2020,A1

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Technical Information

• 1,4-Addition of an Amine to a Conjugated Enone • 1,4-Addition of an Amine to a Conjugated Enone • Acidity of Phenols • Alkyl Halide Occurrence • Amides Can Be Converted into Aldehydes • Amine Synthesis from Nitriles • Amine Synthesis from Nitriles • Amines Convert Acyl Chlorides into Amides • Amines Convert Esters into Amides • An Alkane are Prepared from an Haloalkane • Azide Reduction by LiAlH4 • Azide Reduction by LiAlH4 • Basicity of Amines • Benzylic Oxidation • Birch Reduction • Birch Reduction of Benzene • Blanc Chloromethylation • Buchwald-Hartwig C-N Bond and C-O Bond Formation Reactions • Chan-Lam Coupling Reaction • Chichibabin Reaction • Complete Benzylic Oxidations of Alkyl Chains • Complete Benzylic Oxidations of Alkyl Chains • Conjugate Additions of p-Benzoquinones • Conversion of Amino with Nitro • Decomposition of Arenediazonium Salts to Give Phenols • Deprotonation of Methylbenzene • Diazo Coupling • Diazotization Reaction • DIBAL Attack Nitriles to Give Ketones • Directing Electron-Donating Effects of Alkyl • Electrophilic Chloromethylation of Polystyrene • Electrophilic Substitution of the Phenol Aromatic Ring • Enamine Formation • Etherification Reaction of Phenolic Hydroxyl Group • Formation of an Amide from an Amine and a Carboxylic Acid • Formation of an Amide from an Amine and a Carboxylic Acid • Friedel-Crafts Alkylation of Benzene with Acyl Chlorides • Friedel-Crafts Alkylation of Benzene with Carboxylic Anhydrides • Friedel-Crafts Alkylation of Benzene with Haloalkanes • Friedel-Crafts Alkylation Using Alkenes • Friedel-Crafts Alkylations of Benzene Using Alkenes • Friedel-Crafts Alkylations Using Alcohols • Friedel-Crafts Reaction • Groups that Withdraw Electrons Inductively Are Deactivating and Meta Directing • Halogenation of Benzene • Halogenation of Phenols • Hemiaminal Formation from Amines and Aldehydes or Ketones • Hemiaminal Formation from Amines and Aldehydes or Ketones • Hofmann Elimination • Hofmann Rearrangement • Hydride Reductions • Hydrogenation to Cyclohexane • Hydrogenolysis of Benzyl Ether • Hydrolysis of Imines to Aldehydes and Ketones • Imine Formation from Amines and Aldehydes or Ketones • Kolbe-Schmitt Reaction • Leuckart-Wallach Reaction • Mannich Reaction • Methylation of Ammonia • Methylation of Ammonia • Nitration of Benzene • Nitrosation of Amines • Nucleophilic Aromatic Substitution • Nucleophilic Aromatic Substitution with Amine • Oxidation of Alkyl-substituted Benzenes Gives Aromatic Ketones • Oxidation of Phenols • Pechmann Coumarin Synthesis • Peptide Bond Formation with DCC • Petasis Reaction • Preparation of Aldehydes and Ketones • Preparation of Alkylbenzene • Preparation of Amines • Preparation of LDA • Reactions of Amines • Reactions of Benzene and Substituted Benzenes • Reduction of an Amide to an Amine • Reduction of an Amide to an Amine • Reductive Amination • Reductive Amination • Reductive Removal of a Diazonium Group • Reimer-Tiemann Reaction • Reverse Sulfonation——Hydrolysis • Ring Opening of Azacyclopropanes • Ring Opening of Azacyclopropanes • Ring Opening of Oxacyclobutanes • Specialized Acylation Reagents-Vilsmeier Reagent • Strecker Synthesis • Sulfonation of Benzene • Synthesis of 2-Amino Nitriles • The Acylium Ion Attack Benzene to Form Phenyl Ketones • The Claisen Rearrangement • The Nitro Group Conver to the Amino Function • Ugi Reaction • Vilsmeier-Haack Reaction

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P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

Physical hazards
Code	Phrase
H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
H203	Explosive; fire, blast or projection hazard
H204	Fire or projection hazard
H205	May mass explode in fire
H220	Extremely flammable gas
H221	Flammable gas
H222	Extremely flammable aerosol
H223	Flammable aerosol
H224	Extremely flammable liquid and vapour
H225	Highly flammable liquid and vapour
H226	Flammable liquid and vapour
H227	Combustible liquid
H228	Flammable solid
H229	Pressurized container: may burst if heated
H230	May react explosively even in the absence of air
H231	May react explosively even in the absence of air at elevated pressure and/or temperature
H240	Heating may cause an explosion
H241	Heating may cause a fire or explosion
H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
H251	Self-heating; may catch fire
H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
H270	May cause or intensify fire; oxidizer
H271	May cause fire or explosion; strong oxidizer
H272	May intensify fire; oxidizer
H280	Contains gas under pressure; may explode if heated
H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
H304	May be fatal if swallowed and enters airways
H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
H313	May be harmful in contact with skin
H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
H350	May cause cancer
H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

[ CAS No. 163733-99-1 ] {[proInfo.proName]}

Quality Control of [ 163733-99-1 ]

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[ 163733-99-1 ] Synthesis Path-Upstream 1~5

[ 163733-99-1 ] Synthesis Path-Downstream 1~32

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Fluorinated Building Blocks

Aryls

Amines

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[ 163733-99-1 ]